ORION: Gene Silencing, PCSK9 & LDL Cholesterol

Dr. Tashko, an esteemed lipidologist in Montgomery County, Maryland, delivers comprehensive healthcare, emphasizing holistic approaches to patients' well-being, with a particular focus on lipid-related conditions and their management.

March 2020 NEJM / December 2021 FDA Approved

Cardiovascular Disease Prevalence and Significance

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death in the United States and worldwide. In the US alone, a person dies from cardiovascular-related causes every 33 seconds. Therefore, it is crucial to develop new therapies that aim to reduce the risk of cardiovascular disease.

The “Bad Cholesterol”

One critical factor that can be modified to mitigate the risk of heart disease is the level of low-density lipoprotein (LDL) cholesterol in the blood. Extensive research conducted over the past few decades has confirmed that lower LDL cholesterol (LDL-C) measurements directly decrease the likelihood of developing atherosclerosis. Consequently, individuals with lower LDL-C concentrations in their blood are less likely to experience cardiovascular events like heart attacks or strokes.

Guidelines on Cholesterol Goals

In line with this principle, national and international guidelines have been shifting towards setting even lower targets for LDL cholesterol. For instance, the 2023 American Diabetes Association standards recommend an LDL-C goal of less than 55 mg/dL for patients with diabetes and established cardiovascular disease.

Cholesterol Medications

  • Statins. The fundamental approach to preventing cardiovascular disease revolves around adopting healthier lifestyle habits. While lifestyle changes play a crucial role, medications, particularly statins, have emerged as a pivotal strategy in helping individuals reduce or prevent ASCVD. Unfortunately, there are cases where lifestyle adjustments and statins may not be enough to reach the desired LDL-C target. Some patients may also experience intolerance or side effects from statin treatment, making it unsuitable for their needs.
  • PCSK9 Inhibitors. As a result, alternative medical methods have been developed to address high LDL-C concentrations in the blood. It has been discovered that increased levels of a molecule called PCSK9 in the serum can interfere with the function of LDL receptors in the liver, which play a crucial role in clearing LDL-C from the blood. Currently, two FDA-approved medications, Repatha and Praluent, are available, and they work by binding specifically to serum PCSK9, rendering it ineffective. This process effectively reduces LDL cholesterol levels.

Novel Technology for Developing Cholesterol Medications

Another, more potent approach to lowering blood PCSK9 concentrations involves inhibiting its production at its source in the liver by a new breakthrough technology called gene silencing. A newly FDA-approved medication called Leqvio serves this precise purpose. Leqvio is a small interfering RNA (siRNA) that is injected subcutaneously twice a year at a dose of 284 mg. The siRNA binds to the messenger RNA (mRNA) responsible for synthesizing the PCSK9 protein, effectively silencing the gene and preventing PCSK9 production.

  • Leqvio (Inclisiran). Leqvio has received FDA approval as an additional therapy to diet and maximally tolerated statin medications for adults diagnosed with either heterozygous familial hypercholesterolemia (HeFH) or severe ASCVD who require further reduction of LDL cholesterol. Heterozygous familial hypercholesterolemia affects approximately 1 in 250 individuals in the general population, who typically have cholesterol levels 2-3 times higher than normal.
  • Leqvio underwent rigorous testing in three clinical trials, involving approximately 3,500 participants with severely high cholesterol or clinically established ASCVD. The combined findings of the three trials demonstrated that the addition of Leqvio to statin medications resulted in an additional 40-50% reduction in LDL-C after 17 months of therapy. In comparison, the placebo group only achieved a 1-8% reduction in LDL-C.

It is important to note that the clinical trials of Leqvio did not focus on preventing ASCVD outcomes such as heart attacks and strokes but rather on reducing blood LDL cholesterol concentrations. Common side effects of Leqvio included reactions at the injection site, urinary tract infections, and joint stiffness.

Significance of Leqvio

Leqvio represents a significant and valuable addition to the range of treatment options for individuals with advanced cardiovascular disease or severe hypercholesterolemia who have been unable to reach their target LDL cholesterol levels despite lifestyle changes and maximum tolerated statin therapy. A notable advantage of Leqvio is its convenience since it only requires two subcutaneous injections per year in a medical office setting.

Dr. Tashko

Dr. Tashko is a distinguished lipidologist based in Montgomery County, Maryland, renowned for expertise in cholesterol and triglyceride management. Specializing in conditions like hypercholesterolemia and hypertriglyceridemia, he employs cutting-edge lipid testing methods, such as NMR and lipoprotein little a analysis. Dr. Tashko is dedicated to preventing atherosclerosis and cardiovascular disease through personalized approaches. His arsenal includes medications like Repatha, Praluent, Leqvio, and Fenofibrate, chosen based on patients' unique profiles. With a strong commitment to patient care, Dr. Tashko's holistic strategies incorporate lifestyle adjustments and evidence-based treatments, making him a prominent figure in the field. His exceptional care and focus on lipid-related concerns continue to positively impact the health and well-being of his patients.